Central People's Hospital of Zhanjiang

Abstract Bladder cancer exhibits considerable heterogeneity, posing challenges for prognosis and treatment. In this study, we utilized an integrated approach involving single‐cell RNA sequencing and the Cancer Genome Atlas dataset analysis, combined with in vitro functional assays, to identify key genes associated with bladder cancer progression. A novel three‐gene signature was identified and validated for its prognostic relevance in independent patient samples. Among these genes, FAM3B emerged as the most significant driver, consistently overexpressed in high‐risk patients and strongly associated with poor survival outcomes. Functional assays in bladder cancer cell lines demonstrated that FAM3B promotes cell proliferation, clonogenicity, migration, and invasion. Additionally, the three‐gene signature showed a significant correlation with advanced tumor grade and stage, highlighting its potential utility for clinical risk stratification and personalized treatment strategies. These findings not only enhance our understanding of bladder cancer biology but also underscore the therapeutic potential of targeting FAM3B and the three‐gene signature as prognostic biomarkers.

Autoimmune rheumatic diseases (ARDs) are a diverse group of chronic disorders characterized by immune dysregulation and multi-organ inflammation. B cell receptor (BCR) signaling emerges as a shared, yet heterogeneously regulated, pathogenic axis across these diseases. This dysregulation drives B cell activation, autoantibody production, and ultimately tissue damage. Recent research highlights its involvement in both common and disease-specific mechanisms, which helps explain the wide variation in clinical features and therapeutic responses across ARDs. This review summarizes current evidence establishing BCR signaling as a central regulatory and therapeutic target in rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, IgG4-related disease, and ANCA-associated vasculitis. It integrates mechanistic insights with recent clinical trial data on BCR signaling-targeted therapies, discussing factors that may contribute to variability in therapeutic responses and treatment limitations. Finally, we outline current challenges and future directions for precision medicine in ARDs, with a focus on biomarker-guided strategies and innovative combination therapies to improve patient outcomes.

Abstract Background This study aims to analyze the composition, diversity, and metabolic functions of gut microbiota (GM)-derived outer membrane vesicles (OMVs) in patients with vascular dementia (VaD), to identify potential biomarkers for VaD diagnosis. Methods GM-derived OMVs were isolated from 29 VaD patients and 28 matched controls via ultracentrifugation and characterized using transmission electron microscopy and nanoparticle tracking analysis. PKH26-labeled OMVs were used for in vivo tracking in mouse brains. Microbial composition was profiled by 16S rRNA sequencing, combined with diversity analysis and machine learning. Results VaD-OMVs were widely distributed in multiple cognitive function-related regions of mouse brains. The VaD group showed a decreased Chao1 index and increased coverage. β-diversity (PCoA/PLS-DA) revealed significant structural differences. Conditional pathogens (e.g., Pseudomonas , Acinetobacter ) were enriched, while beneficial bacteria (e.g., Bifidobacterium ) were reduced. Correlation analysis indicated promoting effects of Pseudomonadaceae and inhibitory effects of Faecalibacterium. Metabolic pathways including amino acid, carbohydrate, and nucleotide metabolism were enriched. A random forest model achieved an AUC of 0.74 (95% CI: 0.59–0.88) in classifying VaD. Conclusion VaD is associated with distinct OMV microbial and functional profiles. OMV-based biomarkers show potential for VaD diagnosis.

Given the increasing use of targeted therapies in clinical practice, we aimed to determine the clinically actionable safety profiles of second-line tyrosine kinase inhibitors (TKIs) in advanced hepatocellular carcinoma (HCC) by analysing adverse drug reactions (ADRs) reported in the WHO-VigiAccess database. Retrospective descriptive analysis of ADR reports for cabozantinib and regorafenib in advanced HCC after first-line failure. Data included patient demographics, geographic distribution, system organ classes (SOCs) and preferred terms (PTs) (MedDRA v24.0). Chi-squared tests were used to compare patient characteristics; head-to-head disproportionality analysis [reporting odds ratio (ROR)] was performed for gastrointestinal (GI) disorders. A total of 51,404 reports were analysed (cabozantinib: 33,846; regorafenib: 17,558). Cabozantinib exhibited a significantly higher proportion of GI disorders (87.2% vs. 60.3%; P<0.001) and higher GI-related ROR [1.31; 95% confidence interval (CI): 1.29-1.33] than regorafenib (0.73; 95% CI: 0.71-0.74). Diarrhoea was the most frequent ADR with cabozantinib (23.7%), whereas fatigue dominated regorafenib reports (16.3%). Death-related ADRs were similar (cabozantinib 6.36%; regorafenib 5.96%). Cabozantinib carries a disproportionately higher risk of severe GI toxicity compared with regorafenib. Clinicians should consider prophylactic anti-diarrhoeal therapy, routine liver-function monitoring, and early dose modifications when initiating cabozantinib, especially in male patients aged 45-64 years. These data supported personalized second-line TKI selection after first-line failure.

Identification of novel targets is critical for the effective management of HCC. UFMylation, a novel ubiquitin-like modification, plays an important role in various biological processes and disease progression. We found that WW domain binding protein 11 (WBP11) is enriched and predicts poor prognosis in HCC. Depletion of WBP11 inhibits the malignancy of HCC cells in vitro and in vivo. Mechanistically, the N-terminal of WBP11 interacts with the RNA recognition motif (RRM) domain of Non-POU-domain-containing octamer-binding protein (NONO) and enhances glycolysis in HCC cells. WBP11 maintains protein stability of NONO by competitively inhibiting UFM1-specific ligase 1 (UFL1)-induced UFMylation of NONO at Lys198. Enforced-NONO expression restores the suppression of growth and metastasis caused by WBP11 depletion or UFL1 overexpression. Overall, our study identifies a key role of the WBP11-NONO axis in HCC progression and reveals the importance of UFMylation in cancer, highlighting potential anticancer strategies by targeting the WBP11-regulated new types of posttranslational modifications.

ETS1 and FLI1 exhibit distinct roles in immunoregulation and autoimmune pathogenesis. Previous transethnic genome-wide meta-analyses incorporating our Han Chinese population established significant associations between ETS1 single-nucleotide polymorphisms (SNPs) and susceptibility to primary biliary cholangitis (PBC). In our earlier genome-wide association study (GWAS), ten SNPs within the ETS1 and FLI1 loci demonstrated modest yet suggestive associations with PBC susceptibility in the Han Chinese population. To validate these putative risk loci, we conducted an independent replication study of rs10893900 and rs2246290 using a separate Han Chinese PBC cohort. A meta-analysis combining data from two stages identified rs10893900 as a genome-wide significant variant (P = 4.55 × 10-8, OR = 1.19, 95% CI = 1.12-1.27). Subsequent functional characterization identified rs10893900 as a susceptibility-associated functional variant. Based on the literature review, we summarized ETS1 variants' susceptibility to human autoimmune diseases, including SLE, RA, and PBC, and evaluated these variants in silico analysis. Importantly, our research implicates the importance of ETS1 involving JAK-STAT signaling pathway, expanding the understanding of pathological mechanisms of PBC.

The SSPOP gene, currently classified as a pseudogene in the human genome, encodes the SCO-spondin protein, which plays an important role in human neurodevelopment, although its function remains poorly understood. In this study, we used trio-based whole exome sequencing to identify compound heterozygous SSPOP variants in four children from three unrelated families, including one pair of dizygotic twins. These children exhibited variable phenotypes, including variation in age of onset, seizure semiology, and response to antiseizure medications, along with neurodevelopmental disorders. We demonstrated that SSPOP is a functional gene by confirming its expression at both the transcriptional and protein levels. We analysed 10 brain tissue samples from seven paediatric patients and brain organoids derived from human induced pluripotent stem cells to confirm its expression via qRT-PCR, immunofluorescence and western blotting, supporting its biological function during both pre- and post-natal stages of brain development. In addition, CRISPR-mediated sspo knockout zebrafish demonstrated abnormal neurodevelopment and epileptic discharges in vivo. Together, these findings suggest that SSPOP is a functional gene and a potential contributor to neurodevelopmental disorders and epilepsy.

Abstract Objective: Lung cancer is a leading cause of cancer-related deaths globally, with lung adenocarcinoma (LUAD) showing high incidence in non-smoking cases. Over one million die annually from lung cancer, and LUAD presents treatment challenges due to complex biological behavior, variability in therapeutic responses, and pronounced heterogeneity (within tumor cells and the microenvironment). This study integrates single-cell RNA sequencing (scRNA-Seq) and genome-wide association study (GWAS) data to identify LUAD-associated cell subpopulations and core genes, offering insights into pathogenesis and potential therapeutic targets/prognostic biomarkers. Methods: The GSE196303 single-cell transcriptomic dataset (3 adjacent normal, 3 tumor tissues) was analyzed via Seurat and Harmony for clustering, annotation, and batch correction. Combined with GWAS summary data (1002 cases, 462008 controls), scPagwas identified trait-associated subpopulations. Using TCGA-LUAD bulk RNA-seq (541 tumors, 59 adjacent tissues) and clinical data, BayesPrism quantified cell subtype abundance. Limma, WGCNA, somatic mutation analysis, and immune infiltration assessment (ssGSEA, CIBERSORT) explored clinical associations. Drug sensitivity was predicted via oncoPredict, with survival analysis and Cox regression screening prognostic markers. Results: Eleven cell subpopulations were identified; CD8+ T cells had significantly higher trait-related scores (TRS, P&lt;0.05). BayesPrism showed CD8+ T cell abundance was upregulated in LUAD and linked to favorable prognosis (P&lt;0.05). Effector CD8+ T cell abundance correlated with gender, TNM stage, and survival, with high-abundance patients more sensitive to drugs like Savolitinib (P&lt;0.05). TP53 and STK11 mutations associated with effector CD8+ T cell abundance. WGCNA and differential expression screening identified GNG7 as a core gene linked to effector CD8+ T cells, with high expression significantly improving survival (P=0.004). Conclusion: CD8+ T cells are a core LUAD subpopulation, with abundance correlating with clinical characteristics and the immune microenvironment. GNG7 is a core gene associated with effector CD8+ T cells.